Download 2. Mendelian Pedigree patterns

Genes in Pedigrees & Populations
1. Monogenic versus multifactorial inheritance:
• Over 6000 Mendelian characters are known in
humans (OMIM databse
www.ncbi.nlm.nih.gov/Omim/
• Multifactorial trait may involve a small number
of loci (oligogenic) or many loci (polygenic)
• Dichotomous characters are known as
susceptibility genes while quantitative or
continuous characters are known as quantitative
trait loci (QTLs).
2. Mendelian Pedigree patterns:
• Dominance and recessiveness are properties
of traits not genes. Example sickle cell
anemia. Dominance describes the
phenotype of the heterozygotes.
- Males are hemizygous for loci on X and
most Y so the problems of dominance and
recessiveness do not apply to X- and Ylinked characters.
• Five basic Mendelian Pedigree Patterns:
- Autosomal dominant
- Autosomal recessive
- X-limked recessive
- X-linked dominant
- Y-linked
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- X inactivation disturbs the distinction
between dominant & recessive X-linked
conditions (manisfesting heterozygotes
observed in X-linked recessive conditions).
- Genes in the Xp-Yp 2.6MB homologous
pairing region segregate like autosomal
genes and not like sex-limnked genes and
thus are called pseudoautosomal genes.
• The mode of inheritance of a human trait
requires the compilation of pedigrees from
several families (50 or so) displaying the
same trait. This is because:
- numbers per family are too small
- in recessive traits, # of affected children
are greater than 1 out of 4. This is due to
“biases of ascertainment.”
- genetic counselors should emphasize that
modes of inheritance are hypothesis and not
facts.
• One-gene-one enzyme hypothesis does not apply
in humans because most enzymes are complexes
encoded by many gene loci.
This occurs because of 3 types of heterogeneity:
- Locus heterogeneity
- Allelic heterogeneity
- Clinical heterogeneity
Locus heterogeneity demonstrates complementation
in human syndromes that result from failure of a
complex pathway (e.g. hearing loss)
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• Mitochondrial inheritance is complexed by
matrilineal inheritance and heteroplasmy.
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3. Complications of the basic Mendelian pedigree
patterns:
• Common recessive conditions mimic a dominant
pedigree pattern. Example blood group O (Fig
4.5A).
• Dominant traits fail to manifest which is known as
nonpenetrance (Fig 4.5B, autosomal dominant
trait fails to manifest in some of the offspring).
• Age-related penetrance in late onset diseases (e.g.
Huntington disease) which might be due slow
tissue death or accumulation of noxious
substances (see Fig 4.7).
• Variable expression (Fig 4.5C, autosomal
dominant inheritance of Waardenburg syndrome
shows variable expression).
• Anticipation (a special type of variable
expression) is the tendency of some variable
dominant conditions to become more severe in
successive generations. Geneticists should avoid
misinterpreting anticipation with variable
expression. Anticipation is caused in cases that are
due to unstable expandable trinucleotide repeats
(e.g. Fragile-X) cause by misalignment of such
repeats during crossing over.
• Expression of imprinted genes depends on
parental origin (Fig 4.5D, autosomal dominant
trait manifests only when inherited from the
father; Fig 4.5E, genetic imprinting showing
inheritance of an autosomal dominant syndrome
only from the mother).
• Male lethality may complicate X-linked pedigrees.
In some X-linked dominant conditions, the
absence of the normal allele is lethal before birth.
Thus affected males are not born (Fig 4.5F).
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• New mutations may complicate pedigree analysis.
When a normal couple with no relevant family
history have a child with severe abnormalities,
pedigree analysis becomes very difficult. The
problem may be autosomal recessive, autosomal
dominant with a new mutation, X-linked recessive,
or nongenetic. See Fig 4.5H as an example.
• New mutation can lead to mosaicism, at the somatic,
gonadal (germinal), or at both the somatic and
germinal levels. Fig 8 shows a new mutation in Xlinked recessive Duchenne muscular dystrophy.
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• Molecular analysis can be used to clarify
mosicism cause by new mutations. In males
(not in females) direct testing of gametes is
feasible to detect germinal new mutations.
In females somatic tissues can be used for
analysis.
• A negative result using somatic tissue does
not rule out germline mosaicism, but a
positive result, in conjugation with an
affected child, proves it (Fig. 4.9)
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• Chimeras are the result fusion of two zygotes to
form a single embryo or the limited colonization
of one twin by cells from non-identical co-twin
(Fig. 4.10)
• Chimerism is proved by finding too many parental
alleles at several gene loci when examining pooled
tissue samples. Example, blood-grouping centers
occasionally discover chimeras among normal
donors. Some interesx patients turn out to be
46,XY/46,XX.
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4. Genetics of multifactorial characters:
• Polygenic characters are the result of the
additive effect of a large number of
individual alleles (in different loci) and this
results in a Normal (Gaussian) distribution
in the pouplation. See Fig. 4.11
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5. Factors affecting gene frequencies:
• For a single gene locus, two alleles A1 and
A2occupy that locus and the allele (gene)
frequencies are:
A1 = p
A2 = q
A1 + A2 = 1.0
• The genotype frequencies in that locus are:
p2 + 2pq + q2 = 1.0
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